Use of IκB-kinase inhibitors in pain therapy

ABSTRACT

The present invention relates to the use of IκB-kinase Inhibitors and methods for the prophylaxis and therapy for treating pain comprising administering such compounds.

This application claims the benefit of U.S. Provisional Application No.60/434,628, filed Dec. 19, 2002. The content of U.S. ProvisionalApplication 60/434,628 is incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to the use of IκB-kinase inhibitors for treatingpain.

BACKGROUND OF THE INVENTION

Patent applications WO 01/00610, WO 01/30774 and WO 01/68648, thecontent of each of which is incorporated herein by reference, describecompounds which are able to modulate NFκB. NFκB is a heterodimerictranscription factor which is able to activate a large number of geneswhich encode, inter alia, proinflammatory cytokines such as IL-1, IL-2,TNFα or IL-6. NFκB is present in the cytosol of cells, where it iscomplexed with its naturally occurring inhibitor IκB. Stimulation of thecells, for example by cytokines, leads to the IκB being phosphorylatedand subsequently broken down proteolytically. This proteolytic breakdownleads to the activation of NFκB, which then migrates into the nucleus ofthe cell, where it activates a large number of proinflammatory genes.

In diseases such as rheumatoid arthritis (in connection withinflammation), osteoarthritis, asthma, cardiac infarction, Alzheimer'sdiseases or atherosclerosis, NFκB is activated to beyond the normalextent. The inhibition of NFκB is also of value in the treatment ofcancer since it is used in such treatment to augment the cytostatictherapy. It has been demonstrated that pharmaceuticals such asglucocorticoids, salicylates or gold salts, which are used in thetherapy of rheumatism, inhibit the NFκB-activating signal chain atvarious points or interfere directly with the transcription of thegenes. The first step in said signal cascade is the breakdown of IκB.This phosphorylation is regulated by the specific IκB kinase.

Pharmaceuticals belonging to a large number of different substancegroups are employed in treating acute and chronic pain. Despite this,the therapy of pain has still not been satisfactorily solved even today.This is due, in particular, to the fact that the analgesics which are onthe market do not have a sufficiently powerful effect.

In an endeavor to obtain active compounds for treating pain, it has nowbeen found that it is possible to use IκB-kinase inhibitors for thispurpose. In particular, it has been possible to demonstrate, in themodels employed, a strength of effect which is clearly superior to thatof classical nonsteroidal anti-inflammatory agents.

The invention relates, therefore, to the use of IκB-kinase inhibitorsfor producing pharmaceuticals for treating pain.

The term “pain” is understood as meaning acute pains and chronic pains.The following are examples of chronic pains:

-   chronic musculoskeletal diseases, such as back pains,-   pains associated with menstrual bleeding,-   pains associated with osteoarthritis or rheumatoid arthritis,-   pains associated with intestinal inflammation,-   pains associated with cardiac muscle inflammation,-   pains associated with multiple sclerosis,-   pains associated with neuritis,-   pains associated with carcinomas and sarcomas,-   pains associated with AIDS,-   pains associated with chemotherapy,-   amputation pain,-   trigeminus neuralgia,-   headaches, such as migraine cephalalgia, or-   neuropathic pains, such as post-herpes zoster neuralgia.

The following are examples of acute pains:

-   pains following injuries,-   post-operative pains,-   pains in association with an acute attack of gout, or-   acute pains following jaw-bone surgery interventions.

Examples of IκB-kinase inhibitors are indole derivatives orbenzimidazole derivatives as are described in the patent applications WO01/00610 and WO 01/30774.

SUMMARY OF THE INVENTION

The invention furthermore relates to the use of compounds of the formulaI

and/or a stereoisomeric form of the compound of the formula I and/or aphysiologically tolerated salt of the compound of the formula I, forproducing pharmaceuticals for treating pains, where E is N atom or theradical —C(R¹⁹)—,

-   -   where R¹⁹ is hydrogen atom or the radical R⁹, one of the        substituents R¹, R², R³ and R⁴ is a radical of the formula II,

in which D is —C(O)—, —S(O)— or —S(O)₂—,

-   -   R⁸ is hydrogen atom or —-(C₁-C₄)-alkyl,    -   R⁹ is 1. characteristic radical of an amino acid,        -   2. aryl, in which aryl is unsubstituted or substituted,        -   3. heteroaryl having from 5 to 14 ring members, in which            heteroaryl is unsubstituted or substituted,        -   4. heterocycle having from 5 to 12 ring members, in which            heterocycle is unsubstituted or substituted,        -   5. —(C₁—C₆)-alkyl, in which alkyl is straight-chain or            branched and is unsubstituted or substituted, once, twice or            three times, independently of each other, by            -   5.1 aryl, in which aryl is unsubstituted or substituted,            -   5.2 heteroaryl having from 5 to 14 ring members, in                which heteroaryl is unsubstituted or substituted,            -   5.3 heterocycle having from 5 to 12 ring members, in                which heterocycle is unsubstituted or substituted,            -   5.4 —O—R¹¹,            -   5.5 ═O,            -   5.6 halogen,            -   5.7 —CN,            -   5.8 —CF₃,            -   5.9 —S(O)_(x)—R¹¹, in which x is the integer zero, 1 or                2,            -   5.10 —C(O)—O—R¹¹,            -   5.11 —C(O)—N(R¹¹)₂,            -   5.12 —C(O)—R¹¹,            -   5.13 —N(R¹¹)₂,            -   5.14 —(C₃-C₆)-cycloalkyl,            -   5.15 radical of the formula

or

-   -   -   -   5.16 radical of the formula

-   -   R¹¹ is a) hydrogen atom,        -   b) (C₁-C₆)-alkyl, in which alkyl is unsubstituted or            substituted once, twice or three times            -   1. aryl, in which aryl is unsubstituted or substituted,            -   2. heteroaryl having from 5 to 14 ring members,            -   3. heterocycle having from 5 to 12 ring members,            -   4. halogen,            -   5. —N—(C₁-C₆)_(n)-alkyl, in which n is the integer zero,                1 or 2 and alkyl is unsubstituted or substituted once,                twice or three times, independently of each other, by                halogen or by —C(O)—OH,            -   6. —O—(C₁-C₆)-alkyl or            -   7. —C(O)—OH,        -   c) aryl, in which aryl is unsubstituted or substituted,        -   d) heteroaryl having from 5 to 14 ring members, or        -   e) heterocycle having from 5 to 12 ring members, and, in the            case of (R¹¹)₂, R¹¹ has, independently of each other, the            meanings of a) to e),    -   Z is 1. aryl, in which aryl is unsubstituted or substituted,        -   2. heteroaryl having from 5 to 14 ring members, in which            heteroaryl is unsubstituted or substituted,        -   3. heterocycle having from 5 to 12 ring members, in which            heterocycle is unsubstituted or substituted,        -   4. —(C₁-C₆)-alkyl, in which alkyl is substituted or            unsubstituted        -   5. —C(O)—R¹¹,        -   6. —C(O)—O—R¹¹ or        -   7 —C(O)—N(R¹¹)₂, or

R⁸ and R⁹ form, together with the nitrogen atom and carbon atom to whichthey are in each case bonded, a heterocyclic ring of the formula IIa,

in which D and Z are defined as in formula II,

-   -   A is nitrogen atom or the radical —CH₂—,    -   B is oxygen atom, sulfur atom, nitrogen atom or the radical        —CH₂—,    -   X is oxygen atom, sulfur atom, nitrogen atom or the radical        —CH₂—,    -   Y is absent or is oxygen atom, sulfur atom, nitrogen atom or the        radical —CH₂—, or    -   X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or        1,4-diazine radical,        where the ring system which is formed by N, A; X, Y, B and        carbon atom does not contain more than one oxygen atom, X is not        oxygen atom, sulfur atom or nitrogen atom when A is nitrogen        atom, does not contain more than one sulfur atom, and contains        1, 2, 3 or 4 nitrogen atoms, and where an oxygen atom and a        sulfur atom are not present simultaneously,        where the ring system which is formed by N, A, X, Y, B and        carbon atom is unsubstituted or is substituted, once, twice or        three times, independently of each other, by (C₁-C₈)-alkyl, in        which alkyl is unsubstituted or substituted, once or two times,        by    -   1.1. —OH,    -   1.2. —(C₁-C₈)-alkoxy,    -   1.3. halogen,    -   1.4. —NO₂,    -   1.5. —NH₂,    -   1.6. —CF₃,    -   1.7. methylenedioxyl,    -   1.8 —C(O),    -   1.9. —C(O)—CH₃,    -   1.10. —(C₁-C₄)-alkoxycarbonyl,    -   1.11. —CN,    -   1.12. —C(O)—OH,    -   1.13. —C(O)—NH₂,    -   1.14. tetrazolyl,    -   1.15. phenyl,    -   1.16. phenoxy,    -   1.17. benzyl or    -   1.18. benzyloxy or

R⁹ and Z form, together with the carbon atoms to which they are in eachcase bonded, a heterocyclic ring of the formula IIc,

in which D, R⁸ and R¹¹ are defined as in formula II,

-   -   T is oxygen atom, sulfur atom, nitrogen atom or the radical        —CH₂—,    -   W is oxygen atom, sulfur atom, nitrogen atom or the radical        —CH₂—,    -   V is absent or is oxygen atom, sulfur atom, nitrogen atom or the        radical —CH₂—, or    -   T and V or V and W together form a phenyl, 1,2-diazine,        1,3-diazine or 1,4-diazine radical,        where the ring system which is formed by N, T, V, W and two        carbon atoms does not contain more than one oxygen atom, does        not contain more than one sulfur atom and contains 1, 2, 3 or 4        nitrogen atoms, where an oxygen atom and a sulfur atom are not        present simultaneously, and where the ring system which is        formed by N, T, V, W and two carbon atoms is unsubstituted or is        substituted, once, twice or three times, independently of each        other, by the substituents which are defined above under 1.1. to        1.18., and        the other substituents R¹, R², R³ and R⁴ in each case are,        independently of each other,    -   1. hydrogen atom,    -   2. halogen,    -   3. —(C₁-C₆)-alkyl,    -   4. heteroaryl having from 5 to 14 ring members, in which        heteroaryl is unsubstituted or substituted,    -   5. heterocycle having from 5 to 12 ring members, in which        heterocycle is unsubstituted or substituted,    -   6. —NO₂,    -   7. —CN,    -   8. —O—(C_(O)-C₄)-alkylaryl,    -   9 —O—(C₁-C₄)-alkyl,    -   10. —O—R¹¹,    -   11. —N(R¹¹)₂,    -   12. —S(O)_(r)—R¹¹, in which r is the integer zero, 1 or 2, or    -   13. —CF₃,        R⁵ is 1. hydrogen atom,    -   2. —OH or    -   3. ═O, and        R⁶ is 1. aryl, in which aryl is unsubstituted or substituted,    -   2. phenyl which is substituted once or twice by        -   2.1 —CN,        -   2.2 —NO₂,        -   2.3 —O—(C₁-C₄)-alkyl,        -   2.4 —N(R¹¹)₂,        -   2.5 —NH—C(O)—R¹¹,        -   2.6 —S(O)_(s)—R¹¹, in which s is the integer zero, 1 or 2,        -   2.7 —C(O)—R¹¹ or        -   2.8 —(C₁-C₄)-alkyl-NH₂,            3. heteroaryl having from 5 to 14 ring members, is            unsubstituted or is substituted once, twice or three times,            or            4. heterocycle having from 5 to 12 ring members, is            unsubstituted or is substituted once, twice or three times.

The invention furthermore relates to the use, according to theinvention, of the compound of the formula I, where

-   E is N atom or the radical —C(R¹⁹)—,    -   where R¹⁹ is hydrogen atom or the radical R⁹,        one of the substituents R¹, R², R³ and R⁴ is a radical of the        formula II, in which-   D is —C(O)—, —S(O)— or —S(O)₂—,-   R⁸ is hydrogen atom or —(C₁-C₄)-alkyl,-   R⁹ is 1. a characteristic radical of an amino acid which is derived    from a naturally occurring □-amino acid of the group alanine,    valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan,    serine, threonine, cysteine, methionine, asparagine, glutamine,    lysine, histidine, arginine, glutamic acid and aspartic acid,    -   2. a characteristic radical of an amino acid which is derived        from an amino acid which is not naturally occurring, such as        2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid,        2,4-diaminobutyric acid, 2,3-diaminopropionic acid,        1,2,3,4,-tetrahydroisoquinoline-1-carboxylic acid,        1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic        acid, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, sarcosine,        pipecolic acid, 2-aminoheptanoic acid, hydroxylysine,        N-methylisoleucine, 6-N-methyllysine, norleucine,        N-methylvaline, norvaline, ormithine, allo-isoleucine,        4-hydroxyproline, allo-hydroxylysine, allo-threonine,        3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine),        homocysteine, homophenylalanine, homocysteic acid,        2-amino-3-phenylaminoethylpropionic acid,        2-amino-3-phenylaminopropionic acid, homotryptophan, cysteic        acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine,        3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine,        3-fluorophenylalanine, 2-fluorophenylalanine,        4-chlorophenylalanine, 4-nitrophenylalanine, cyclohexylalanine,        4-aminophenylalanine, citrulline, 5-fluorotryptophan,        5-methoxytryptophan, methionine sulfone, methionine sulfoxide or        —NH—NR¹¹—CON(R¹¹)₂, in which R¹¹ is defined as below,    -   3. aryl, from the group anthryl, biphenylyl, 2-biphenylyl,        3-biphenylyl, 4-biphenylyl, fluorenyl, naphthyl, 1-naphthyl,        2-naphthyl or phenyl, in which aryl is unsubstituted or        substituted once, twice or three times by identical or different        radicals from the series —C(O)—(C₁-C₄)-alkyl, —C(O), ═O,        —NH—(C₁-C₄)-alkyl, —NH—((C₁-C₄)-alkyl)₂, —(C₁-C₈)-alkyl,        —(C₁-C₈)-alkoxy, halogen, nitro, amino, trifluoromethyl,        hydroxyl, —CF₃, hydroxy-(C₁-C₄)-alkyl, such as hydroxymethyl or        1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy,        formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl,        —(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy,        —S(O)_(x)—R¹¹ in which x is the integer zero, 1 or 2,        —O—(C₁-C₄)-alkyl, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl,        —NH—C(O)—(C₁-C₄)-alkyl or tetrazolyl,    -   4. heteroaryl having from 5 to 14 ring members, in which        heteroaryl is unsubstituted or substituted and, as a radical, is        derived from the group azepine, azetidine, benzimidazole,        benzodioxolane, 2-benzofuran, benzothiazole, benzothiophene,        2-benzothiophene, 2-benzoxazole, β-carboline, quinoxaline,        quinazoline, quinoline, 2-quinoxaline, cyclohepta[b]-5-pyrrole,        diazepine, dihydropyridine, 3-hydroxypyrro-2,4-dione, imidazole,        4-imidazole, imidazolidine, imidazoline, indazole, indole,        isoquinoline, isoindole, isothiazole, isothiazolidine,        isoxazole, 2-isoxazolidine, isoxazolidine, isoxazolone,        methylimidazole, 3-(N-methylpyrrolidine), morpholine, oxazole,        1,3,4-oxadiazole, oxadiazolidinedione, oxadiazolone,        5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole,        1,2,3,5-oxathiadiazole-2-oxide, 1-oxo-1,2-dihydro-3-isoquinol,        phenylpyrrole, 5-phenyl-2-pyrrole, phthalazine, piperazine,        piperidine, pyrazine, pyrazole, pyrazoline, pyrazolidine,        pyrazoline, pyridazine, pyrimidine, pyridine, pyridyl-N-oxide,        2-pyrrole, 3-pyrrole, pyrrolidine, pyrroline,        4,5,6,7-tetrahydro-2-indole, tetrahydrothienyl, tetrazole,        thiadiazole, thiazole, thiomorpholine, thiophene, triazole,        triazolone or triazole,    -   in which heteroaryl is unsubstituted or substituted once, twice        or three times by identical or different radicals which are        derived from the series —C(O)—(C₁-C₄)-alkyl, —C(O), ═O,        —NH—(C₁-C₄)-alkyl, —NH—((C₁-C₄)-alkyl)₂, —(C₁-C₈)-alkyl,        —(C₁-C₈)-alkoxy, halogen, nitro, amino, trifluoromethyl,        hydroxyl, —CF₃, hydroxy-(C₁-C₄)-alkyl such as hydroxymethyl or        1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy,        formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl,        —(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy,        —S(O)_(x)—R¹¹, in which x is the integer zero, 1 or 2,        —O—(C₁-C₄)-alkyl, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl,        —NH—C(O)—(C₁-C₄)-alkyl or tetrazolyl,    -   5. —(C₁-C₆)-alkyl in which alkyl is straight-chain or branched        and is unsubstituted or substituted once, twice or three times,        independently of each other, by        -   5.1 aryl, in which aryl is defined as above,        -   5.2 heteroaryl having from 5 to 14 ring members, in which            heteroaryl is defined as above,        -   5.3 —(C₃-C₆)-cycloalkyl,        -   5.4 —O—R¹¹,        -   5.5 ═O,        -   5.6 halogen,        -   5.7 —CN,        -   5.8 —CF₃,        -   5.9 —S(O)_(x)R¹¹, in which x is the integer zero, 1 or 2,        -   5.10 —C(O)—O—R¹¹,        -   5.11 —C(O)—N(R¹¹)₂,        -   5.12 —C(O)—R¹¹,        -   5.13 —N(R¹¹)₂,        -   5.14 a radical of the formula

or

-   -   -   5.15 a radical of the formula

in which

-   -   -   R¹¹ is a) hydrogen atom,            -   b) (C₁-C₆)-alkyl in which alkyl is unsubstituted or                substituted once, twice or three times by                -   1. aryl, in which aryl is defined as above,                -   2. heteroaryl having 5 to 14 ring members, in which                    heteroaryl is defined as above,                -   3. halogen,                -   4. —N—(C₁-C₆)_(n)-alkyl, in which n is the integer                    zero, 1 or 2 and alkyl is unsubstituted or                    substituted once, twice or three times,                    independently of each other, by halogen or by                    —C(O)—OH,                -   5. —O—(C₁-C₆)-alkyl or                -   6. —C(O)—OH,            -   c) aryl, in which aryl is defined as above, or            -   d) heteroaryl having from 5 to 14 ring members, in which                heteroaryl is defined as above, and        -   in the case of (R¹¹)₂, the radical R¹¹ has, independent of            each other, the meaning of a) to d),

-   Z is 1. aryl in which aryl is defined as above,    -   2. heteroaryl having from 5 to 14 ring members, in which        heteroaryl is defined as above,    -   3. —(C₁-C₆)-alkyl, in which alkyl is straight-chain or branched        and is substituted once or twice by phenyl or —OH,    -   4. —C(O)—O—R¹¹, or    -   5. —C(O)—N(R¹¹)₂, and the other substituents R¹, R², R³ and R⁴        in each case are, independently of each other,    -   1. hydrogen atom,    -   2. halogen,    -   3. —(C₁-C₄)-alkyl,    -   4. heteroaryl having from 5 to 14 ring members, in which        heteroaryl is as defined above,    -   5. —(C₁-C₆)-alkyl,    -   6. —NO₂,    -   7. —CN,    -   8. —O—(C₀-C₄)-alkyl-aryl, in which aryl is defined as above,    -   9. —O—(C₁-C₄)-alkyl,    -   10. —OR¹¹,    -   11. —N(R¹¹)₂,    -   12. —S(O)_(x)—R¹¹, in which x is the integer zero, 1 or 2, or    -   13. —CF₃,

-   R⁵ is 1. hydrogen atom,    -   2. —OH, or    -   3. ═O, and

-   R⁶ is 1. aryl, from the group naphthyl, 1-naphthyl, 2-naphthyl,    phenyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,    anthryl or fluorenyl,    -   in which aryl is unsubstituted or substituted, once, twice or        three times, by identical or different radicals from the series        —C(O)—(C₁-C₄)-alkyl, —C(O), ═O, —NH—(C₁-C₄)-alkyl,        —NH—((C₁-C₄)-alkyl)₂, —(C₁-C₈)-alkyl, —(C₁-C₈)-alkoxy, halogen,        nitro, amino, trifluoromethyl, hydroxyl, —CF₃,        hydroxy-(C₁-C₄)-alkyl such as hydroxymethyl or 1-hydroxyethyl or        2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl,        cyano, hydroxycarbonyl, aminocarbonyl, —(C₁-C₄)-alkoxycarbonyl,        phenyl, phenoxy, benzyl, benzyloxy, —S(O)_(x)—R¹¹, in which x is        the integer zero, 1 or 2, —O—(C₁-C₄)-alkyl, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, —NH—C(O)—(C₁-C₄)-alkyl or tetrazolyl, or    -   2. heteroaryl having from 5 to 14 ring members, in which        heteroaryl is defined as above and in which heteroaryl is        unsubstituted or substituted, once, twice or three times, by        identical or different radicals from the series        —C(O)—(C₁-C₄)-alkyl, —C(O), ═O, —NH—(C₁-C₄)-alkyl,        —NH—((C₁-C₄)-alkyl)₂, —(C₁-C₈)-alkyl, —(C₁-C₈)-alkoxy, halogen,        nitro, amino, trifluoromethyl, hydroxyl, —CF₃,        hydroxy-(C₁-C₄)-alkyl such as hydroxymethyl or 1-hydroxyethyl or        2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl,        cyano, hydroxycarbonyl, aminocarbonyl, —(C₁-C₄)-alkoxycarbonyl,        phenyl, phenoxy, benzyl, benzyloxy, —S(O)_(x)—R¹¹, in which x is        the integer zero, 1 or 2, —O—(C₁-C₄)-alkyl, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, —NH—C(O)—(C₁-C₄)-alkyl or tetrazolyl.

The invention furthermore relates to the use, according to theinvention, of the compound of the formula I, where

E is N atom or the radical —C(R¹⁹)—,

-   -   in which R¹⁹ is hydrogen atom, one of the substituents R¹, R²,        R³ and R⁴ is a radical of the formula II, in which

-   R⁸ is hydrogen atom,

-   R⁹ is 1. a characteristic radical of an amino acid from the group    histidine, serine, tryptophan, threonine, cysteine, methionine,    asparagine, glutamine, lysine, arginine, glutamic acid and aspartic    acid, or    -   2. —(C₁-C₆)-alkyl, in which alkyl is straight-chain or branched        and is unsubstituted or substituted, once or twice, by        -   a) phenyl,        -   b) a radical from the group azepine, azetidine,            benzimidazole, benzothiazole, benzothiophene, benzoxazole,            diazepine, imidazole, indole, isothiazole, isoxazole,            morpholine, 1,3,4-oxadiazole,            5-oxo4,5-dihydro-[1,3,4]oxadiazole, oxazole piperidine,            pyrazine, pyrazole, pyridine, pyrimidine, pyrrole,            pyrrolidine, pyrroline, thiazole, thiomorpholine, thiophene            or triazole,        -   c) —NH(R¹¹),        -   d) —C(O)—R¹², in which            -   R¹² is naphthyl, phenyl, morpholinyl or pyrimidinyl,        -   e) —O—R¹¹,        -   f) —N(R¹²)-phenyl, in which R¹² is defined as above,        -   g) —S(O)_(x)—R¹², in which x is zero, 1 or 2, and        -   h) —CN, or        -   i) —(C₃-C₆)-cycloalkyl, and the radicals defined above by            a), b), d) and i) and R¹² are unsubstituted or are            substituted, once or twice, by —OH, —(C₁-C₄)-alkyl, —CF₃,            halogen, —O—(C₁-C₄)-alkyl, —COOH, —C(O)—O—(C₁-C₄)-alkyl,            —NH₂ or —NH—C(O)—(C₁-C₄)-alkyl,

-   Z is 1. a heteroaryl radical from the group    3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline,    indazole, isothiazole, isothiazolidine, isoxazole, isoxazolidine,    2-isoxazolidine, isoxazolone, morpholine, 1,3,4-oxadiazole,    oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide,    oxazole, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole,    5-oxo-1,2,4-thiadiazole, piperazine, pyrazine, pyrazole,    pyrazolidine, pyrazoline, pyridazine, pyrimidine, tetrazole,    thiadiazole, thiazole, thiomorpholine, triazole or triazolone, and    -   the heteroaryl radical is unsubstituted or substituted, once,        twice or three times, independently of each other, by    -   1.1 —C(O)—R¹⁵, in which R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl,    -   1.2 —(C₁-C₄)-alkyl,    -   1.3 —O—R¹⁵, in which R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl,    -   1.4 —N(R¹⁵)—R¹⁶, in which R¹⁵ and R¹⁶ are, independently of each        other, hydrogen atom or —(C₁-C₄)-alkyl,    -   1.5 halogen, or    -   1.6 keto radical,    -   2. —C(O)—R¹⁵, in which R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl,    -   3. —C(O)—R¹⁵, in which R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl,        or    -   4. —C(O)—N(R¹⁵)—R¹⁶, in which R¹⁵ and R¹⁶ are, independently of        each other, hydrogen atom or —(C₁-C₄)-alkyl,

-   R¹¹ is 1. —(C₁-C₄)-alkyl,    -   2. R¹³or,    -   3. —N(R¹³)₂, in which R¹³ is, independently of each other,    -   a) hydrogen atom,    -   b) —(C₁-C₆)-alkyl,    -   c) —(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl,    -   d) —(C₁-C₆)-alkyl-N(R¹⁵)₂, in which R¹⁵ is defined as above, or    -   e) —(CO—C₄)-alkyl which is substituted, once or twice, by        imidazolyl, morpholinyl or phenyl, or

-   R⁸ and R⁹ form, together with the nitrogen atom and carbon atom to    which they are in each case bonded, a ring of the formula IIa from    the group pyrrole, pyrroline, pyrrolidine, pyridine, piperidine,    piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole,    imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine,    oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine,    isothiazole, thiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides,    oxadiazolone, isoxazolone, triazolones, oxadiazolidinedione,    triazole, which are substituted by F, CN, CF₃ or COO—(C₁-C₄)-alkyl,    3-hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles,    1,3,4-oxadiazole, isothiazolidine, thiomorpholine, indazole,    thiadiazole, benzimidazole, quinoline, triazole, phthalazine,    quinazoline, quinoxaline, purine, pteridine, indole,    tetrahydroquinoline, tetrahydroisoquinoline and isoquinoline, or

-   R⁹ and Z form, together with the carbon atoms to which they are in    each case bonded, a ring of the formula IIc from the group pyrrole,    pyrroline, pyrrolidine, pyridine, piperidine, piperylene,    pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole,    pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole,    isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole,    thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole,    benzimidazole, quinoline, triazole, phthalazine, quinazoline,    quinoxaline, purine, pteridine, indole, tetrahydroquinoline,    tetrahydroisoquinoline, isoquinoline, tetrazole,    1,2,3,5-oxathiadiazole-2-oxides, oxadiazolone, isoxazolone,    triazolones, oxadiazolidinedione, triazole, which are substituted by    F, CN, CF₃ or COO—(C₁-C₄)-alkyl, 3-hydroxypyrro-2,4-diones,    1,3,4-oxadiazole and 5-oxo-1,2,4-thiadiazole and    the other substituents R¹, R², R³ and R⁴ in each case are,    independently of each other,    -   1. hydrogen atom,    -   2. halogen,    -   3. —(C₁-C₄)-alkyl,    -   4. —CN,    -   5. —NO₂,    -   6. —O—(C₀-C₄)-alkyl-phenyl,    -   7. —O—(C₁-C₄)-alkyl,    -   8. —N—(C₀-C₄)-alkyl-phenyl,    -   9. —N—(C₁-C₄)-alkyl or    -   10. —CF₃,

-   R⁵ is 1. hydrogen atom,    -   2. —OH, or    -   3. ═O, and

-   R⁶ is 1. phenyl, substituted, once or twice, by    -   1.1 —CN,    -   1.2 —NO₂,    -   1.3 —O—(C₁-C₄)-alkyl, or    -   1.4 —NH₂, or    -   2. is pyridine or pyrimidine,    -   where pyridine or pyrimidine is unsubstituted or substituted,        once, twice or three times, by identical or different radicals        from the series —C(O)—(C₁-C₄)-alkyl, —C(O), ═O,        —NH—(C¹-C₄)-alkyl, —NH—((C₁-C₄)-alkyl)₂, —(C₁-C₈)-alkyl,        —(C₁-C₈)-alkoxy, halogen, nitro, amino, trifluoromethyl,        hydroxyl, —CF₃, hydroxy-(C₁-C₄)-alkyl such as hydroxymethyl or        1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy,        formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl,        —(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy,        —S(O)_(x)—R¹¹, in which x is the integer zero, 1 or 2,        —O—(C₁-C₄)-alkyl, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl,        —NH—C(O)—(C₁-C₄)-alkyl or tetrazolyl.

The invention furthermore relates to the use, according to theinvention, of the compound of the formula I,

-   where E is the radical —C(R¹⁹)—,    -   in which R¹⁹ is hydrogen atom or R⁹,        one of the substituents R¹, R, R³ and R⁴ is a radical of the        formula II in which D is —C(O)—,-   R⁸ is hydrogen atom,-   Z is 5-oxo4,5-dihydro-[1,3,4]oxadiazole, —C(O)—OH or —C(O)—NH₂,-   R⁹ is 1. —(C₁-C₄)-alkyl, in which alkyl is straight-chain or    branched and is substituted once or twice, independently of each    other, by    -   1.1 —S(O)—R¹¹, where R¹¹ is defined as below,    -   1.2 —N(R¹¹)₂, where R¹¹ is defined as below, or    -   1.3 pyrrole, or    -   2. the characteristic radical of an amino acid from the group        histidine, tryptophan, serine, threonine, cysteine, methionine,        asparagine, glutamine, lysine, arginine, glutamic acid and        aspartic acid,-   R¹¹ is a) hydrogen atom,    -   b) —(C₁-C₆)-alkyl, in which alkyl is unsubstituted or        substituted, once or three times, independently of each other,        by halogen, or    -   c) phenyl, in which phenyl is unsubstituted or substituted, once        to three times, independently of each other, by halogen or        —(C₁-C₄)-alkyl,        the other substituents R¹, R², R³ and R⁴ are in each case        hydrogen atom,-   R⁵ is hydrogen atom, and-   R⁶ is phenyl, pyridine or pyrimidine,    -   where phenyl, pyridine or pyrimidine is unsubstituted or        substituted, once, twice or three times, by identical or        different radicals from the series —C(O)—(C₁-C₄)-alkyl, —C(O),        ═O, —NH—(C₁-C₄)-alkyl,    -   —NH—((C₁-C₄)-alkyl)₂, —(C₁-C₈)-alkyl, —(C₁-C₈)-alkoxy, halogen,        nitro, amino, trifluoromethyl, hydroxyl, —CF₃,        hydroxy-(C₁-C₄)-alkyl such as hydroxymethyl or 1-hydroxyethyl or        2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl,        cyano, hydroxycarbonyl, aminocarbonyl, —(C₁-C₄)-alkoxycarbonyl,        phenyl, phenoxy, benzyl, benzyloxy, —S(O)_(x)—R¹¹, in which x is        the integer zero, 1 or 2, —O—(C₁-C₄)-alkyl, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, —NH—C(O)—(C₁-C₄)-alkyl or tetrazolyl.

The invention furthermore relates to the use, according to theinvention, of the compound of the formula Ia

and/or a stereoisomeric form of the compound of the formula Ia and/or aphysiologically tolerated salt of the compound of the formula Ia, where

-   E and M are identical or different and are, independently of each    other N atom or CH-   R21 and R31 are identical or different and are, independently of    each other,    -   1. hydrogen atom,    -   2. halogen,    -   3. —(C₁-C₄)-alkyl,    -   4. —CN,    -   5. —CF₃,    -   6. —OR¹⁵, in which R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl,    -   7. —N(R¹⁵)—R¹⁶, in which R¹⁵ and R¹⁶ are, independently of each        other, hydrogen atom or —(C₁-C₄)-alkyl,    -   8. —C(O)—R¹⁵, in which R¹⁵ is hydrogen atom or C₁-C₄)-alkyl, or    -   9. —S(O)_(x)—R¹⁵ in which x is the integer zero, 1 or 2, and R¹⁵        is hydrogen atom or —(C₁-C₄)-alkyl,-   R²² is 1. a heteroaryl radical from the group    3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline,    indazole, isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine,    isoxazolidine, isoxazolone, morpholine, oxazole, 1,3,4-oxadiazole,    oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide,    5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole,    piperazine, pyrazine, pyrazole, pyrazoline, pyrazolidine,    pyridazine, pyrimidine, tetrazole, thiadiazole, thiazole,    thiomorpholine, triazole or triazolone, and    -   the heteroaryl radical is unsubstituted or is substituted once,        twice or three times, independently of each other, by    -   1.1 —C(O)—R¹⁵, in which R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl,    -   1.2 —(C₁-C₄)-alkyl,    -   1.3 —O—R¹⁵, in which R¹⁵ is hydrogen atom or C₁-C₄)-alkyl,    -   1.7 —N(R¹⁵)—R¹⁶, in which R¹⁵ and R¹⁶ are, independently of each        other, hydrogen atom or —(C₁-C₄)-alkyl,    -   1.8 halogen, or    -   1.9 keto radical,    -   2. —C(O)—R¹⁵, in which R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl,    -   3. —C(O)—OR¹⁵, in which R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl,        or    -   4. —C(O)—N(R¹⁷)—R¹⁸, in which R¹⁷ and R¹⁸ are, independently of        each other, hydrogen atom, —(C₁-C₄)-alkyl-OH, —O—(C₁-C₄)-alkyl        or —(C₁-C₄)-alkyl,-   R²³ is hydrogen atom or —(C₁-C₄)-alkyl,-   R²⁴ is 1. a heteroaryl radical from the group pyrrole, furan,    thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,    isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides,    triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones,    triazoles, 3-hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles,    pyridine, pyrazine, pyrimidine, indole, isoindole, indazole,    phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline,    cinnoline, β-carboline and benzo fused cyclopenta derivatives or    cyclohexa derivatives of these heteroaryl radicals,    -   where the heteroaryl radical is unsubstituted or is substituted,        once, twice or three times, independently of each other, by        —(C₁-C₅)-alkyl, —(C₁-C₅)-alkoxy, halogen, nitro, amino,        trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl,        methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,        hydroxycarbonyl, aminocarbonyl or —(C₁-C₄)-alkoxycarbonyl, or    -   2. an aryl radical from the group phenyl, naphthyl, 1-naphthyl,        2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl and        4-biphenylyl, anthryl or fluorenyl, and the aryl radical is        unsubstituted or substituted, once, twice or three times,        independently of each other, by —(C₁-C₅)-alkyl, —(C₁-C₅)-alkoxy,        halogen, nitro, amino, trifluoromethyl, hydroxyl,        hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, formyl,        acetyl, cyano, hydroxycarbonyl, aminocarbonyl or        —(C₁-C₄)-alkoxycarbonyl.

The invention furthermore relates to the use, according to theinvention, of the compound of the formula Ia, where

-   E and M are identical or different and are, independently of each    other, N atom or CH,-   R21 and R31 are identical or different and, independently of each    other, are defined as above under 1. to 9.,-   R22 is 1. a heteroaryl radical from the group imidazole,    isothiazole, isoxazole, 2-isoxazolidine, isoxazolone,    1,3,4-oxadiazole, oxadiazolidinedione, 1,2,3,5-oxadiazolone,    oxazole, 5-oxo4,5-dihydro-[1,3,4]oxadiazole, tetrazole, thiadiazole,    thiazole, triazole or triazolone, and the heteroaryl radical is    unsubstituted or is substituted once, twice or three times,    independently of each other, by    -   1.1 keto radical,    -   1.2 halogen or    -   1.3 —(C₁-C₂)-alkyl, or    -   2. —C(O)—N(R¹⁷)—R¹⁸, in which R¹⁷ and R¹⁸ are, independently of        each other, hydrogen atom, —(C₁-C₄)-alkyl-OH, —O—(C₁-C₄)-alkyl,        or —(C₁-C₄)-alkyl,-   R²³ is hydrogen atom, methyl or ethyl,-   R²⁴ is 1. a heteroaryl radical from the group of the unsaturated,    partially saturated or completely saturated rings which are derived    from pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan,    thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,    triazole or isothiazole,    -   where the heteroaryl radical is unsubstituted or substituted,        once, twice or three times, independently of each other, by        —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxy, F, Cl, I, Br, nitro, amino,        trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl,        methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,        hydroxycarbonyl, aminocarbonyl or —(C₁-C₄)-alkoxycarbonyl, or    -   2. phenyl and phenyl is unsubstituted or is substituted once,        twice or three times, independently of each other, by F, Cl, I,        Br, CF₃, —OH, —(C₁-C₄)-alkyl or —(C₁-C₄)-alkoxy.

The invention furthermore relates to the use, according to theinvention, of the compoundN-[(S)-2-diphenylamino-1-(5-oxo4,5-dihydro-[1,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamideorN-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methyl-aminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamide.

Definition of Terms

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings.

“Patient” includes both human and other mammals.

“Pharmaceutically effective amount” is meant to describe an amount of acompound, composition, medicament or other active ingredient effectivein producing the desired therapeutic effect.

“Optionally substituted” means either unsubstituted or substituted oneor more times by substituents, which may be the same, or different.

The term “halogen” is understood as meaning fluorine, chlorine, bromineor iodine. The terms “—(C₁-C₈)-alkyl”, “—(C₁-C₆)-alkyl” and“—(C₁-C₄)-alkyl” are understood as meaning hydrocarbon radicals whosecarbon chain is straight-chain or branched and contains from 1 to 8,from 1 to 6 and from 1 to 4 carbon atoms, respectively, such as methyl,ethyl, propyl, butyl, tert-butyl, pentyl, hexyl, heptyl or octyl. Theterm “—(Co)-alkyl” is understood as meaning a covalent bond. Examples ofcyclic alkyl radicals are 3- to 6-membered monocycles such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The phrase “R⁸ and R⁹ form, together with the nitrogen atom and carbonatom to which they are in each case bonded, a heterocyclic ring of theformula IIa” is understood as meaning radicals which are derived frompyrrole, pyrroline, pyrrolidine, imidazole, pyrazole, oxazole,isoxazole, tetrazole, isoxazoline, isoxazolidine, morpholine, thiazole,isothiazole, isothiazoline, purine, isothiazolidine, thiomorpholine,pyridine, piperidine, pyrazine, piperazine, pyrimidine, pyridazine,indole, isoindole, indazole, benzimidazole, phthalazine, quinoline,isoquinoline, quinoxaline, quinazoline, cinnoline, pteridine,triazolones, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, oxadiazolones,isoxazolones, oxadiazolidinediones, triazoles, which are substituted byF, —CN, —CF₃ or —C(O)—O—(C₁-C₄)-alkyl, 3-hydroxypyrro-2,4-diones,5-oxo-1,2,4-thiadiazoles, imidazolidine, carboline and benzofusedderivatives of these heterocycles.

The phrase “R⁹ and Z form, together with the carbon atoms to which theyare in each case bonded, a heterocyclic ring of the formula IIc ” isunderstood as meaning radicals which [lacuna] from the group pyrrole,pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine,pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline,imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole,2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole,isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole,quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine,pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline,isoquinoline, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, oxadiazolone,isoxazolone, triazolone, 3-hydroxypyrro-2,4-diones, 1,3,4-oxadiazole and5-oxo-1,2,4-thiadiazole, oxadiazolidinedione, triazole, which areunsubstituted or substituted by F, CN, CF₃ or C(O)—O—(C₁-C₄)-alkyl.

The phrase “heteroaryl radical from the group of the unsaturated,partially saturated or completely saturated rings which are derived frompyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene,imidazole, pyrazole, oxazole, isoxazole, thiazole and isothiazole”, isunderstood as meaning, for example, compounds such as piperazine,pyrazoline, imidazoline, pyrazolidine, imidazolidine,tetrahydropyridine, isoxazoline, isoxazolidine, morpholine,isothiazoline, isothiazolidine, tetrahydro-1,4-thiazine and piperidine.

The term “aryl” is understood as meaning aromatic hydrocarbon radicalshaving from 6 to 14 carbon atoms in the ring. Examples of —(C₆-C₁₄)-arylradicals are phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl,biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl,anthryl and fluorenyl. Biphenylyl radicals, naphthyl radicals and, inparticular, phenyl radicals are preferred aryl radicals. Aryl radicals,in particular phenyl radicals, can be substituted once or more thanonce, preferably once, twice or three times, by identical or differentradicals, preferably by radicals from the series —(C₁-C₈)-alkyl, inparticular —(C₁-C₄)-alkyl, —(C₁-C₈)-alkoxy, in particular—(C₁-C₄)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,hydroxycarbonyl, aminocarbonyl, —(C₁-C₄)-alkoxycarbonyl, phenyl,phenoxy, benzyl, benzyloxy and tetrazolyl. The same applies, in acorresponding manner, for example, for radicals such as arylalkyl orarylcarbonyl. Arylalkyl radicals are, in particular, benzyl and also 1-and 2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and9-fluorenylmethyl. Substituted arylalkyl radicals are, for example,benzyl radicals and naphthylmethyl radicals which are substituted, inthe aryl moiety, by one or more —(C₁-C₈)-alkyl radicals, in particular—(C₁-C₄)-alkyl radicals, for example 2-, 3- and 4-methylbenzyl,4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3,5-dimethylbenzyl,pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-methyl-1-naphthylmethyl,and 1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl, benzylradicals and naphthylmethyl radicals which are substituted, in the arylmoiety, by one or more —(C₁-C₈)-alkoxy radicals, in particular—(C₁-C₄)-alkoxy radicals, for example 4-methoxybenzyl,4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl and2,3,4-trimethoxybenzyl, nitrobenzyl radicals, for example 2-, 3- and4-nitrobenzyl, halobenzyl radicals, for example 2-, 3- and4-chlorobenzyl, 2-, 3- and 4-fluorobenzyl, 3,4-dichlorobenzyl,pentafluorobenzyl and trifluoromethylbenzyl radicals, for example 3- and4-trifluoromethylbenzyl and 3,5-bis(trifluoromethyl)benzyl.

In monosubstituted phenyl radicals, the substituent can be located inthe 2 position, the 3 position or the 4 position. Doubly substitutedphenyl can be substituted in the 2,3 position, the 2,4 position, the 2,5position, the 2,6 position, the 3,4 position or the 3,5 position. Intriply substituted phenyl radicals, the substituents can be located inthe 2,3,4 position, the 2,3,5 position, the 2,4,5 position, the 2,4,6position, the 2,3,6 position or the 3,4,5 position.

The comments made with regard to the aryl radicals apply, in acorresponding manner, to divalent arylene radicals, for example tophenylene radicals, which can be present, for example, as 1,4-phenyleneor as 1,3-phenylene. Phenylene-(C₁-C₆)-alkyl is, in particular,phenylenemethyl (—C₆H₄—CH₂—) and phenyleneethyl, (C₁-C₆)-alkylenephenyl,in particular methylenephenyl (—CH₂—C₆H₄—). Phenylene-(C₂-C₆)-alkenylis, in particular, phenyleneethenyl and phenylenepropenyl.

The phrase “heteroaryl having from 5 to 14 ring members” means a radicalof a monocyclic or polycyclic aromatic system having from 5 to 14 ringmembers which contains 1, 2, 3, 4 or 5 heteroatoms as ring members.Examples of heteroatoms are N, O and S. If several heteroatoms arepresent, they may be identical or different. Heteroaryl radicals canalso be substituted, once or more than once, preferably once, twice orthree times, by identical or different radicals from the series—(C₁-C₈)-alkyl, in particular —(C₁-C₄)-alkyl, —(C₁-C₈)-alkoxy, inparticular —(C₁-C₄)-alkoxy, halogen, nitro, —N(R¹⁰)₂, trifluoromethyl,hydroxyl, hydroxy-(C₁-C₄)-alkyl, such as hydroxymethyl or 1-hydroxyethylor 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano,hydroxycarbonyl, aminocarbonyl, —(C₁-C₄)-alkoxycarbonyl, phenyl,phenoxy, benzyl, benzyloxy and tetrazolyl. Heteroaryl having from 5 to14 ring members is preferably a monocyclic or bicyclic aromatic radicalwhich contains 1, 2, 3 or 4, in particular 1, 2 or 3, identical ordifferent heteroatoms from the series N, O and S, and which can besubstituted by 1, 2, 3 or 4, in particular 1 to 3, identical ordifferent substituents from the series —(C₁-C₆)-alkyl, —(C₁-C₆)-alkoxy,fluorine, chlorine, nitro, —N(R¹⁰)₂, trifluoromethyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy,benzyloxy and benzyl. Particularly preferably, heteroaryl is amonocyclic or bicyclic aromatic radical having from 5 to 10 ringmembers, in particular a 5-membered to 6-membered monocyclic aromaticradical which contains 1, 2 or 3, in particular 1 or 2, identical ordifferent heteroatoms from the series N, O and S and which can besubstituted by 1 or 2 identical or different substituents from theseries —(C₁-C₄)-alkyl, halogen, hydroxyl, —N(R¹)₂, —(C₁-C₄)-alkoxy,phenyl, phenoxy, benzyloxy and benzyl.

The term “heterocycle having from 5 to 12 ring members” means amonocyclic or bicyclic 5-membered to 12-membered heterocyclic ring whichis partially saturated or completely saturated. Examples of heteroatomsare N, O and S. The heterocycle is unsubstituted or is substituted byidentical or different substituents at one or more carbon atoms or atone or more heteroatoms. These substituents have been defined above inconnection with the heteroaryl radical. In particular, the heterocyclicring is substituted at carbon atoms, once or more than once, for exampleonce, twice, three times or four times, by identical or differentradicals from the series —(C₁-C₈)-alkyl, for example —(C₁-C₄)-alkyl,—(C₁-C₈)-alkoxy, for example —(C₁-C₄)-alkoxy, such as methoxy,phenyl-(C₁-C₄)-alkoxy, for example benzyloxy, hydroxyl, oxo, halogen,nitro, amino or trifluoromethyl and/or is substituted at the ringnitrogen atom(s) in the heterocyclic ring by —(C₁-C₈)-alkyl, for example—(C₁-C₄)-alkyl such as methyl or ethyl, by optionally substituted phenylor phenyl-(C₁-C₄)-alkyl, for example benzyl. Nitrogen heterocycles canalso be present as N-oxides or as quaternary salts.

Examples of the terms heteroaryl having from 5 to 14 ring members andheterocycle having from 5 to 12 ring members are radicals which arederived from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole,isoxazole, thiazole, isothiazole, tetrazole,1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones,isoxazolone, oxadiazolidinedione, triazole, which are substituted by F,—CN, —CF₃ or —C(O)—O—(C₁-C₄)-alkyl, 3-hydroxypyrro-2,4-diones,5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole,isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline, -carboline and benzo fused, cyclopenta fused,cyclohexa fused or cyclohepta fused derivatives of these heterocycles.Particular preference is given to the radicals 2- or 3-pyrrolyl,phenylpyrrolyl, such as 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl,4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4- or-5-imidazolyl, 1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3-or 4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-,5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl,1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl,cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolinyl, 1-, 3- or4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl,2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or benzothiazolyl ordihydropyridinyl, pyrrolidinyl, for example 2- or3-(N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl,tetrahydrothienyl and benzodioxolanyl.

DETAILED DESCRIPTION OF THE INVENTION

The general structural formula of α-amino acids is as follows:

The α-amino acids differ from each other in the radical R which, withinthe context of the present application, is designated the“characteristic radical” of an amino acid. When R⁹ denotes thecharacteristic radical of amino acid, use is preferably made of thecharacteristic radicals of the following naturally occurring α-aminoacids: glycine, alanine, valine, leucine, isoleucine, phenylalanine,tyrosine, tryptophan, serine, threonine, cysteine, methionine,asparagine, glutamine, lysine, histidine, arginine, glutamic acid andaspartic acid. Particular preference is given to histidine, tryptophan,serine, threonine, cysteine, methionine, asparagine, glutamine, lysine,arginine, glutamic acid and aspartic acid. In addition, amino acidswhich do not occur naturally, such as 2-aminoadipic acid, 2-aminobutyricacid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid,2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimellicacid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine,2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid,hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine,N-methylvaline, norvaline, norleucine, ornithine, alloisoleucine,allothreonine, allohydroxylysine, 4-hydroxyproline, 3-hydroxyproline,3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine,homocysteine, homocysteic acid, homotryptophan, cysteic acid,3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine,2-amino-3-phenylaminopropionic acid, 2-amino-3-phenylaminoethylpropionicacid, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenyl-alanine,4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine,2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine,4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan,5-methoxytryptophan, methionine sulfone, methionine sulfoxide or—NH—NR¹¹—C(O)N(R¹¹)₂, which are also substituted, where appropriate, arealso preferred characteristic radicals of amino acid which are employedas the radical R⁸. When amino acids which occur naturally, and alsoamino acids which do not occur naturally, possess a functional groupsuch as amino, hydroxyl, carboxyl, mercapto, guanidyl, imidazolyl orindolyl, this group can also be protected.

The N-protecting groups which are customary in peptide chemistry, forexample protecting groups of the urethane type, benzyloxycarbonyl (Z),t-butyloxycarbonyl (Boc), 9-fluorenyloxycarbonyl (Fmoc),allyloxycarbonyl (Aloc), or of the acid amide type, in particularformyl, acetyl or trifluoroacetyl, and also of the alkyl type, forexample benzyl, are preferably used as suitable protecting groups forthis purpose. When an imidazole radical is present in R⁸, the sulfonicacid derivative of the formula IV, which is employed for the sulfonamideformation, serves, for example, as the group for protecting theimidazole nitrogen, which group can be eliminated once again in thepresence of bases such as sodium hydroxide.

The compounds of the formulae I, Iaand Ibare prepared as described inpatent applications WO 01/00610 and WO 01/30774, the content of each ofwhich is incorporated herein by reference. The starting compounds forthe chemical reactions are known or can be readily prepared usingmethods known from the literature.

EMBODIMENTS

Due to the pharmacological properties, which are evident in the modelsemployed, of the IκB-kinase inhibitors which are used in accordance withthe invention, said inhibitors are suitable for being employed in allforms of pain, in particular in association with pains in whichinflammatory processes play a role.

The pharmaceuticals according to the invention can be administeredorally, by inhalation, rectally or transdermally or by means ofsubcutaneous, intraarticular, intraperitoneal or intravenous injection.Oral or intraarticular administration is preferred.

The invention also relates to a process for producing a pharmaceuticalwhich comprises bringing at least one compound of the formulae I or Ia,together with a pharmaceutically suitable and physiologically toleratedexcipient and, where appropriate, other suitable active compounds,additives or auxiliary substances, into a suitable form foradministration.

Examples of suitable solid or galenic preparation forms are granules,powders, sugar-coated tablets, tablets, (micro)capsules, suppositories,syrups, juices, suspensions, emulsions, drops or injectable solutions,and also preparations with protracted active compound release, in thepreparation of which customary auxiliary substances, such as carriersubstances, disintegrants, binders, coating agents, swelling agents,glidants or lubricants, flavorings, sweeteners and solubilizers areused. Frequently employed auxiliary substances which may be mentionedare magnesium carbonate, titanium dioxide, lactose, mannitol and othersugars, talc, milk protein, gelatin, starch, cellulose and itsderivatives, animal and vegetable oils, such as cod liver oil, sunfloweroil, groundnut oil or sesame oil, polyethylene glycol and solvents, suchas sterile water and monohydric or polyhydric alcohols, such asglycerol. The pharmaceutical preparations are preferably produced andadministered in dosage units, with each unit containing as the activeconstituent a particular dose of the compound of the formula I accordingto the invention. In the case of solid dosage units, such as tablets,capsules, sugar-coated tablets or suppositories, this dose can be up toabout 1000 mg, preferably from about 50 mg to 300 mg, and, in the caseof injection solutions in ampoule form, up to about 300 mg, preferablyfrom about 10 mg to 100 mg. Depending on the activity of the compoundaccording to the formulae I or Ia, daily doses of from about 20 mg to1000 mg of active compound, preferably of from about 100 mg to 500 mg,are indicated for treating an adult patient of about 70 kg in weight.However, higher or lower daily doses may also possibly be appropriate.The daily dose can be administered either by means of a once-onlyadministration in the form of a single dosage unit, or of severalsmaller dosage units, or by means of the multiple administration ofsubdivided doses at predetermined intervals.

As a rule, mass-spectroscopic methods (FAB-MS, ESI-MS) are used fordetermining end products. Temperatures are given in degrees centigrade;RT denotes room temperature (from 22° C. to 26° C.). Abbreviations whichare used are either explained or correspond to the customaryconventions. The invention is explained in more detail below with theaid of examples.

EXAMPLES Preparation Examples

A.1.) Synthesis of the Amino Acid (methyl(S)-2-amino-3-diphenylaminopropionate (5))

N-Benzyloxycarbonyl-L-serine-β-lactone (2)

54.8 g (0.209 mol) of triphenylphosphine were suspended in 600 ml ofacetonitrile and the mixture was cooled down to −35° C. to −45° C. whileexcluding moisture. 36.4 g (0.209 mol) of diethyl azodicarboxylate wereadded dropwise at this temperature within the space of 50 minutes. Themixture was subsequently stirred at −35° C. for 15 minutes. A solutionof 50 g (0.209 mol) of N-benzyloxycarbonyl-L-serine (1) in 500 ml ofacetonitrile was then slowly added dropwise to this mixture such thatthe temperature did not rise above −35° C. The mixture was then stirredat 5° C. for 12 h. In order to terminate the reaction, the reactionsolution was freed from the solvent under reduced pressure and the crudeproduct was purified by means of medium-pressure chromatography onsilica gel. (DCM/AcCN: 25/1). 20.8 g ofN-benzyloxycarbonyl-L-serine-β-lactone (2) were obtained after thesolvent had been removed; yield 45%; (see also Org. Synth. 1991 (70) 1ff.) in fine needles.

Empirical formula C₁₁H₁₁NO₄; M.W.=221.2; MS (M+H) 222.1; ¹H NMR(DMSO-d₆) 4.30 (m, 1H), 4.45 (m, 1H), 5.10 (s, 2H), 5.22 (m, 2H), 7.45(m, 5H), 8.20 (d, J=9.8 Hz, 1H).

(S)-2-Benzyloxycarbonylamino-3-diphenylaminopropionic Acid (3)

5.0 g (22.6 mmol) of serine lactone (2) were mixed by stirring with 20 g(118.2 mmol) of diphenylamine, and the mixture was heated at 100° C. for2 h. The crude product was purified by means of medium-pressurechromatography on silica gel. (DCM/methanol: 9/1, then EA/n-heptane:4/1). 3.65 g (yield 42%) of pure2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (3) were obtainedafter the solvent had been removed.

Empirical formula C₂₃H₂₂N₂O₄; M.W.=390.44; MS (M+H) 391.2; ¹H NMR(DMSO-d₆) 3.85 (m, 1H), 4.18 (m, 1H), 4.3 (m, 1H), 4.9 (m, 2H), 6.9 (m,5H), 7.25 (m, 10H).

Methyl (S)-benzyloxycarbonylamino-3-diphenylaminopropionate (4)

6.5 ml (89.1 mmol) of thionyl chloride were added dropwise, at −5° C.,to 75 ml of methanol and the mixture was stirred for 15 min. 3.6 g (9.22mmol) of 2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (3),dissolved in 75 ml of methanol, were then added and the mixture wasstirred at room temperature for a further 3 hours (h). After thesolvents had been evaporated, the residue was taken up in ethyl acetateand extracted with sodium carbonate solution. The purification by meansof flash chromatography (n-heptane/ethyl acetate 7:3) yielded 2.76 g(50% yield) of methyl 2-benzyloxycarbonylamino-3-diphenylaminopropionate(4).

Empirical formula C₂₄H₂₄N₂O₄; M.W.=404.47; MS (M+H) 405.2; ¹H NMR(DMSO-d₆) 3.58 (s, 3H), 3.95 (m, 1H), 4.18 (m, 1H), 4.4 (m, 1H), 4.95(m, 2H), 6.9 (m, 6H), 7.3 (m, 9H), 7.85 (d, J=9.8 Hz, 1H).

Methyl (S)-2-amino-3-diphenylaminopropionate (5)

In order to eliminate the Z protecting group, 2.7 g (6.68 mmol) of theZ-protected derivative (4) were dissolved in 500 ml of methanol, and 100mg of catalyst (10% Pd(OH)₂—C) were supplied under a protectiveatmosphere of nitrogen. The inert gas was subsequently displaced with alarge excess of hydrogen and the mixture was shaken for 2 h in thehydrogen atmosphere. In order to terminate the reaction, the catalystwas filtered off and the filtrate was concentrated. 1.65 g (yield: 91%)of methyl 2-amino-3-diphenylaminopropionate (5) were obtained.

Empirical formula C₁₆H₁₈N₂O₂; M.W.=270.32; MS (M+H) 271.2; ¹H NMR(DMSO-d6) 3.45 (s, 3H), 3.58 (m, 1H), 3.8 (m, 1H), 3.95 (m, 1H), 6.9 (m,6H), 7.3 (m, 4H).

A.2.) Synthesis of the Heterocyclic Parent Substance(2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic Acid (10))

1-Dimethylamino-4,4-dimethoxypent-1-en-3-one (8)

100 g (0.76 mol) of 3,3-dimethoxy-2-butanone were stirred, at 120° C.for 48 h, with 90.2 g of N,N-dimethylformamide dimethylacetal (0.76mol). The methanol which was formed during the reaction was continuouslyremoved from the reaction solution by distillation. When the solutionwas cooled, spontaneous crystallization occurred, with thiscrystallization being brought to completion by adding a little heptane.This resulted in 128.24 g of crude product 8 (yield 90%), which wassubjected to reaction without any further purification.

Empirical formula C₉H₁₇NO₃; M.W.=187.24; MS (M+H) 188.2; ¹H NMR(DMSO-d₆) 1.22 (s, 3H), 2.80 (s, 3H), 3.10 (s, 9H), 5.39 (d, J=15 Hz,1H), 7.59 (d, J=15 Hz, 1H).

[4-(1,1-Dimethoxyethyl)pyrimidin-2-yl]methylamine (9)

1.22 g (53 mmol) of sodium were dissolved in 100 ml of absolute ethanol.5.8 g (53 mmol) of methylguanidine hydrochloride and 10 g (53 mmol) of1-dimethylamino4,4-dimethoxypent-1-en-3-one (8) were added, withstirring, to this solution, which was heated at boiling heat for 4 h. Inorder to terminate the reaction, the ethanol was evaporated. The product9, which was obtained in this way, was used for the subsequent reactionwithout any further purification. Yield 11.5 g (58 mmol, quantitative).

Empirical formula C₉H₁₅N₃O₂; M.W.=197.24; MS (M+H) 198.2; ¹H NMR(DMSO-d₆) 1.45 (s, 3H), 2.78 (s, 3H), 3.10 (s, 6H), 6.75 (d, J=3 Hz,1H), 7.0-7.1 (s(b), 1H),8.30(d, J=3 Hz, 1H).

2-(2-Methylaminopyrimidin4-yl)-1H-indole-5-carboxylic Acid (10)

5 g (25 mmol) of [4-(1,1-dimethoxyethyl)pyrimidin-2-yl]methylamine (9)and 3.85 g of 4-hydrazinobenzoic acid were added, while stirring, to 150ml of 50% sulfuric acid, and the mixture was heated at 130° C. for 4 h.The methanol which was formed during the reaction was removedcontinuously from the reaction solution by distillation. After it hadbeen cooled down to 10° C., the reaction mixture was poured onto 200 mlof ice, and the pH was adjusted to about 5.5 using concentrated sodiumhydroxide solution. The precipitate of sodium sulfate and productmixture which was formed in this connection was filtered off and thefilter residue was extracted several times with methanol. The combinedmethanol extracts were concentrated and the product was purified bymeans of flash chromatography (DCM/methanol 9:1). Yield: 0.76 g (11%).

Empirical formula C₁₄H₁₃N₄O₂; M.W.=268.28; MS (M+H) 405.2; ¹H NMR(DMSO-d6) 2.95 (s, 3H), 6.90-7.10 (s(b), 1H), 7.18 (d, J=3 Hz, 1H), 7.4(s, 1H), 7.58 (d, J=4.5 Hz, 1H), 7.80 (d, J=4.5 Hz, 1H), 8.30 (s, 1H),7.80 (d, J=4.5 Hz, 1H), 8.38 (d, J=3 Hz, 1H), 11.85 (s, 1H), 12.40-12.60(s(b), 1H).

A.3.) Bringing the Building Blocks Together and SynthesizingN-[(S)-2-diphenylamino-1-(5-oxo4,5-dihydro-[1,3,4]oxadiazol-2-yl)ethyl]-(2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamide(13))

3-Diphenylamino-2-{[2-(2-methylaminopyrimidin4-yl)-1H-indole-5-carbonyl]-(S)-amino}propionicAcid (11)

5.0 g (18.64 mmol) of2-(2-methylaminopyrimidin4-yl)-1H-indole-5-carboxylic acid (10) weredissolved in 1.2 of DMF, after which 7.9 g (24.08 mmol) of TOTU and 7.9ml (46.45 mmol) of ethyldiisopropylamine were added consecutively. Themixture was stirred at 5° C. for 20 min. after which 0.73 g (3.28 mmol)of (S)-2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (5) wasadded to the solution. After 15 h of stirring, the mixture wasconcentrated under reduced pressure, after which the residue was takenup in n-butanol and the organic phase was extracted with a saturatedsolution of sodium hydrogen carbonate in order to separate offbyproducts. After the organic phase had been dried with MgSO₄ andconcentrated, the methyl ester of the title compound was isolated bymeans of flash chromatography on silica gel (DCM:MeOH=19:1). Yield: 4.3g (98%)

Empirical formula C₃₀H₂₈N₆O₃; M.W.=520.22; MS (M+H) 521.3; ¹H NMR(DMSO-d₆) 2.95 (s(b), 3H), 3.60 (s, 3H), 4.19-4.58 (m, 2H), 4.85 (q,1H), 6.90-7.10 (m, 7H), 7.18 (d, J=3 Hz, 1H), 7.25-7.40 (m, 5H), 7.50(d, J=4.5 Hz, 1H), 7.65 (d, J=4.5 Hz, 1H), 8.05 (s, 1H), 8.35 (d, J=3Hz, 1H), 8.70 (d, J=3.75 Hz, 1H), 11.85 (s, 1H).

N-((S)-2-Diphenylamino-1-hydrazinocarbonylethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamide(12)

1.0 g (1.92 mmol) of3-diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carbonyl]-(S)-amino}propionicacid (11) was dissolved in 10 ml of methanol, after which 0.48 g (9.95mmol) of hydrazine hydrate was added and the mixture was stirred at roomtemperature for 15 h. The precipitate of the product (0.3 g) wasseparated off from the mother liquor by filtration. Further hydrazone 12(0.1 g) was isolated from the concentrated mother liquor by flashchromatography on silica gel (DCM:MeOH=19:1). Yield: 0.4 g (40%)

Empirical formula C₂₉H₂₈N₈O₂; M.W.=520.6; MS (M+H) 521.4; ¹H NMR(DMSO-d₆) 2.95 (s(b), 3H), 4.02-4.58 (m, 2H), 4.4 (s, 2H), 4.85 (q, 1H),6.90-7.10 (m, 7H), 7.18 (d, J=3 Hz, 1H), 7.20-7.45 (m, 5H), 7.50 (d,J=4.5 Hz, 1H), 7.62 (d, J=4.5 Hz, 1H), 7.99 (s, 1H), 8.25 (d, J=3 Hz,1H), 8.35 (s(b), 1H), 9.30 (s, 1H), 11.70 (s, 1H).

N-[(S)-2-Diphenylamino-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamide(13)

200 mg (0.384 mmol) ofN-((S)-2-diphenylamino-1-hydrazinocarbonylethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamide(12) were suspended in 20 ml of methylene chloride, and a 20% solutionof phosgene in toluene (0.398 mmol) was added dropwise at 0° C. andwhile stirring. The mixture was stirred at room temperature for afurther 15 h and the solvent was concentrated. The oxadiazolone 13 wassubsequently isolated by flash chromatography on silica gel(DCM:MeOH=9:1). Yield: 160 mg (76%)

Empirical formula C₃₀H₂₆N₈O₃; M.W.=546.6; MS (M+H) 547.3; ¹H NMR(DMSO-d₆) 2.95 (s(b), 3H), 4.02-4.58 (m, 2H), 4.85 (q, 1H), 6.90-7.10(m, 7H), 7.15 (d, J=3 Hz, 1H), 7.20-7.40 (m, 6H), 7.52 (d, J=4.5 Hz,1H), 7.68 (d, J=4.5 Hz, 1H), 8.10 (s, 1H), 8.92 (d, J=3 Hz, 1H), 11.78(s, 1H), 12.15-12.40 (s(b), 1H).

B.) Example Benzimidazole IκB-Kinase Inhibitor B.1.) Synthesis of theAmino Acid (methyl(S)-2-amino-3-diphenylaminopropionate (5)) asDescribed Under A.1.

B.2.) Synthesis of the Heterocyclic Parent Substance(2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxylic acid(19))

4-Dimethylamino-1,1-dimethoxybut-3-en-2-one (16)

300 g (307 ml, 2.54 mol) of methylglyoxal dimethylacetal were stirred,at 110° C. for 4 hours (h), with 303 g (337 ml, 2.54 mol) ofN,N-dimethylformamide dimethylacetal. The methanol which was formedduring the reaction was removed continuously from the reaction solutionby distillation. After having been cooled down, the solution wasextracted with heptane and the solvents were evaporated. This resultedin 303 g of crude product 16 (yield 70%), which was reacted without anyfurther purification.

Empirical formula C₈H₁₅NO₃; M.W.=173.21; MS (M+H) 174.1; ¹H NMR(DMSO-d₆) 2.10 (s, 1H), 2.80 (s, 3H), 3.10 (s, 3H), 3.25 (s, 3H), 3.3(s, 3H), 4.42 (s, 1H), 5.19 (d(b), J=12.8 Hz, 1H), 7.60 (d, J=15 Hz,1H).

(4-Dimethoxymethylpyrimidin-2-yl)methylamine (17)

0.33 g (14.4 mmol) of sodium was dissolved in 50 ml of absolute ethanol.1.57 g (14.4 mmol) of methylguanidine hydrochloride and 2.48 g (14.4mmol) of 4-dimethylamino-1,1-dimethoxybut-3-en-2-one (16) were added,while stirring, to the solution, which was heated at boiling heat for 3h. In order to terminate the reaction, the ethanol was evaporated. Theresulting product 17 was used without any further purification. Yield:2.6 g (quantitative).

Empirical formula C₈H₁₃N₃O₂; M.W.=183.21; MS (M+H) 184.1; ¹H NMR(DMSO-d₆) 2.78 (s, 6H), 3.10 (s, 3H), 5.02 (s, 1H), 6.62 (d, J=3 Hz,1H).

2-Methylaminopyrimidine-4-carbaldehyde (18)

10 g (54 mmol) of (4-dimethoxymethylpyrimidin-2-yl)methylamine (17) weredissolved in 54 ml of 2N sulfuric acid and the solution was heated at80° C. for 3 h while being stirred. After the reaction had cooled down,the reaction solution was carefully brought to a pH of about 9 usingsolid Na₂CO₃ and extracted 3 times with ethanol. After the solvent hadbeen evaporated, the combined dried extracts yielded the title aldehyde18 in 60% yield (4.47 g)

Empirical formula C₆H₇N₃O; M.W.=137.12; MS (M+H) 138.2; ¹H NMR (DMSO-d₆)2.60-2.80 (s(b), 3H), 6.95 (d, J=3 Hz, 1H), 7.40-7.60 (s(b), 8.55 (d,J=3 Hz, 1H).

2-(2-Methylaminopyrimidin4-yl)-1H-benzimidazole-5-carboxylic acid (19)

4.3 g (31.3 mmol) of methylaminopyrimidine-4-carbaldehyde (18) and 4.8 g(31.1 mmol) of 3,4-diaminobenzoic acid were heated at 150° C. for 2 h in300 ml of nitrobenzene. After the mixture had been cooled down to 0° C.,the precipitate of the benzimidazole was separated off from thenitrobenzene by filtration and the product was purified by flashchromatography (DCM/methanol 4:1). Yield: 2.66 g (32%)

Empirical formula C₁₃H₁₁N₅O₂; M.W.=269.28; MS (M+H) 270.2; ¹H NMR(DMSO-d₆) 2.95 (s, 3H), 7.50 (d, J=3 Hz, 1H), 7.75 (d, J=4.5 Hz, 1H),7.90 (d, J=4.5 Hz, 1H), 8.35 (s, 1H), 8.55 (d, J=3 Hz, 1H), 8.70-9.05(s(b), 1H).

3.) Bringing the Building Blocks Together and SynthesizingN-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamide(22)

3-Diphenylamino-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carbonyl]-(S)-amino}propionicAcid (21)

2.6 g (9.6 mmol) of2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxylic acid (20)were dissolved in 300 ml of DMF, after which 3.17 g (9.6 mmol) of TOTUand 1.6 ml (11.6 mmol) of ethyldiisopropylamine were addedconsecutively. The solution was stirred at 5° C. for 20 min, after which2.6 g (9.6 mmol) of(S)-2-benzyloxycarbonylamino-3-diphenylamino-propionic acid (5) wereadded to it. After 16 h of stirring, the mixture was concentrated underreduced pressure, after which the methyl ester 21 was isolated by meansof flash chromatography on silica gel (DCM:MeOH=9:1).

Yield: 1.61 g (32%) Empirical formula C₂₉H₂₇N₇O₃; M.W.=521.58; MS (M+H)522.3; ¹H NMR (DMSO-d₆) 2.95 (s(b), 3H), 3.60 (s, 3H), 4.19-4.40 (m,2H), 4.90 (q, 1H), 6.90-7.10 (m, 6H), 7.25-7.35 (m, 6H), 7.40 (d, J=4.5Hz, 1H), 7.60-7.80 (d(b) 1H), 8.05-8.25 (d(b), 1H), 8.45 (d, J=3 Hz,1H), 8.90 (s(b), 1H), 11.85 (s(b), 1H).

N-((S)-1-Carbamoyl-2-diphenylaminoethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamide(22)

50 ml of (absolute) methanol were saturated with ammonia at 0° C. 0.5 g(0.959 mmol) of3-diphenylamino-2-{[2-(2-methylaminopyrimidin4-yl)-1H-benzimidazole-5-carbonyl]-(S)-amino}propionicacid (21) was added to this mixture and the whole was stirred at roomtemperature for 24 h. After the solvent and excess ammonia had beenevaporated, the amide 22 was isolated by flash chromatography on silicagel (DCM:MeOH=19:1). Yield: 0.43 g (89%)

Empirical formula C₂₉H₂₈N₈O₂; M.W.=506.57; MS (M+H) 507.2; ¹H NMR(DMSO-d₆) 2.95 (s(b), 3H), 4.02-4.35 (m, 2H), 4.85 (q, 1H), 6.80-7.10(m, 6H), 7.15-7.25 (m, 5H), 7.40 (d, J=4.5 Hz, 1H), 7.58 (s(b), 1H),7.68 (s(b), 1H), 8.06-8.19 (d(b), 1H), 8.40-8.58 (m, 2H), 13.10 (s, 1H).

EXPERIMENTAL Pharmacological Examples

IκB-Kinase ELISA:

The activity of the IκB-kinase was determined using an ELISA whichcomprised a biotinylated substrate peptide, which contained the aminoacid sequence in the IκB protein from serine 32 to 36, and a specificpolyclonal or monoclonal antibody (e.g. from New England Biolabs,Beverly, Mass., USA, Cat.: 9240), which only bound to the phosphorylatedform of the IκB peptide. This complex was immobilized on anantibody-binding (protein A-coated) plate and detected using a conjugate30 composed of a biotin-binding protein and HRP (e.g. streptavidin-HRP).The activity was quantified with the aid of a standard curve constructedusing substrate phosphopeptide.

Implementation:

In order to obtain the kinase complex, 10 ml of HeLa S3 cell extractS100 were diluted with 40 ml of 50 mM HEPES, pH 7.5, brought to 40% withrespect to ammonium sulfate and incubated on ice for 30 minutes. Theprecipitated pellet was dissolved in 5 ml of SEC buffer (50 mM HEPES, pH7.5, 1 mM DTT, 0.5 mM EDTA, 10 mM 2-glycerophosphate), centrifuged at 20000 g for 15 minutes and filtered through a 0.22 μm filter. The samplewas loaded onto a 320 ml Superose-6 FPLC column (Amersham PharmaciaBiotech AB, Uppsala, Sweden) which had been equilibrated with SEC bufferand which was operated at 4° C. with a flow rate of 2 ml/min. Thefractions which were located at the migration time of the 670 kDamolecular weight standard were combined for the activation. Activationwas achieved by means of a 45-minute incubation with 100 nM MEKK1Δ, 250μM MgATP, 10 mM MgCl₂, 5 mM dithiothreitol (DTT), 10 mM2-glycerophosphate and 2.5 μM microcystin-LR at 37° C. The activatedenzyme was stored at −80° C. The test substances (2 μl), which weredissolved in DMSO, were preincubated, at 25° C. for 30 minutes, with 43μl of activated enzyme (diluted 1:25 in reaction buffer 50 mM HEPES, pH7.5, 10 mM MgCl₂, 5 mM DTT, 10 mM β-glycerophosphate, 2.5 μMmicrocystin-LR). 5 μl of substrate peptide(biotin-(CH₂)₆-DRHDSGLDSMKD-CONH₂) (200 μM) were then added, after whichthe mixture was incubated for one hour and the reaction was stopped with150 μl of 50 mM HEPES, pH 7.5, 0.1% BSA, 50 mM EDTA, antibody [1:200].100 μl of the stopped reaction mixture or of a standard phosphopeptidedilution series (biotin-(CH₂)₆-DRHDS[PO₃]GLDSMKD-CONH₂) were thentransferred to a protein A plate (Pierce Chemical Co., Rockford, Ill.,USA), after which the plate was incubated for 2 hours while beingshaken. After 3 washing steps with PBS, 100 μl of 0.5 μg/mlstreptavidin-HRP (horseradish peroxidase) (diluted in 50 mM HEPES/0.1%BSA) were added for 30 minutes. After 5 washing steps with PBS, 100 μLof TMB substrate (Kirkegaard & Perry Laboratories, Gaithersburg, Md.,USA) were added and the color development was stopped by adding 100 μLof 0.18 M sulfuric acid. The absorption was measured at 450 nm. Thestandard curve was produced by linear regression corresponding to a4-parameter dose-effect relationship. This standard curve was used toquantify the enzyme activity or its inhibition by the test substances.

The IC₅₀ forN-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamidewas 0.050 μM.

The IC₅₀ forN-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamidewas 0.045 μM.

Pain Assay

The analgesic and antinociceptive activity of the compoundN-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxamide,termed compound 13 in that which follows, was demonstrated in the twofollowing models:

-   1^(st) model: Zymosan-induced paw inflammation in the rat;    -   Parameter: paw withdrawal time or paw withdrawal threshold        during thermal or mechanical stimulation of the hind paw.-   2^(nd) model: Kaolin/carrageenan-induced knee joint inflammation in    the rat;    -   Parameter: reaction of spinal neurons during pressure        stimulation of the knee.        Model 1

Experimental implementation: in short-term anesthesia using isoflurane,1 mg of Zymosan (as a suspension in 100 μl of PBS (phosphate-bufferedsalt solution)) was injected subcutaneously into the middle of theplantar side of one of the experimental animal's hind paws. After that,two different behavioral tests were used to quantitatively determine thedevelopment of a hyperalgesia.

a) Determining the Paw Withdrawal Time during Thermal Stimulation(Hargreaves Test).

The experimental animal was placed in a transparent plastic chamberhaving a glass floor. As soon as the experimental animal was no longermoving, following the reconnaissance phase (about 5 min), an infraredlight source was positioned directly below the hind paw to be stimulatedand switched on. The lamp emitted focused infrared light of increasingintensity, such that the skin temperature of the hind paw increasedalmost linearly. As soon as the animal withdrew the paw, the lampswitched itself off. The temperature of the paw at the time it iswithdrawn has just become unpleasant for the animal; this is referred toas the thermal pain threshold.

b) Determining the paw withdrawal threshold during mechanicalstimulation (von Frey test) The experimental animal was placed in atransparent plastic chamber whose floor consisted of wire-gauze.Punctate pressure of defined strength was produced using calibratednylon fibers, what are termed von Frey hairs. The weakest pressurestimulation during which the animal withdrew its paw determines themechanical pain threshold.

About half an hour before, and at various times after, the Zymosaninjection, the thermal and mechanical pain thresholds were determined onthe right hind paw and on the left hind paw (see Tables 1, 2). Thedecrease in the ipsilateral pain threshold, expressed in % of thecontralateral pain threshold, was then calculated (see Tables 1, 2). Thedegree of hyperalgesia is directly proportional to the magnitude of thisdecrease.

In a control group, the Zymosan injection induced pronounced mechanicaland thermal hyperalgesia (see control data in Tabs. 1 and 2). In anothergroup of animals, which were under short-term isoflurane anesthesia, theabovementioned compound 13 was injected intraperitoneally (i.p.) (ineach case 30 mg/kg in polyethylene glycol/water mixture (PEG/water 1:1)about 15 minutes before, and 2.5 and 5.5 hours after Zymosan injection.From two hours after Zymosan injection onward, the thermal hyperalgesiawas less pronounced in these animals than it was in the control group;after the third administration of the substance, it was no longerpossible to observe any side difference at all in the paw withdrawaltime (Tab. 1). In addition, this effect still persisted for 18 hrs afterthe last administration of the substance.

Compound 13 also significantly reduced the mechanical hyperalgesia. Theeffect set in 1 hour after Zymosan injection and also still persisted 18hrs after the last administration of the substance (see Tab. 2).

The activity of compound 13 is very strong in both test models.Comparative data from a study which was carried out previously show thatcompound 13 reduces the thermal hyperalgesia considerably morepowerfully than does the NSAID diclofenac.

TABLE 1 Change in the paw withdrawal time (%) Time (h) after ZymosanMean value SD compound Mean value SD injection (0) Compound 13 13control control Baseline-0.5 0.0 0.0 0.0 0.0 0.5 −16.6 6.6 −21.4 6.3 1−31.3 14.1 −28.8 11.6 2 −30.2 15.4 −44.8 19.1 3 −15.3 5.3 −49.2 17.9 4−16.0 11.5 −50.6 23.0 5 −9.7 18.6 −46.6 24.8 6 5.0 2.6 −38.4 17.6 7 3.45.8 −29.9 22.1 24 −3.8 7.0 −46.1 18.4

TABLE 2 Change in the paw withdrawal threshold (%) Time (h) afterZymosan Mean value SD compound Mean value SD injection (0) Compound 1313 control control Baseline-0.5 0.0 0.0 0.0 0.0 0.5 −37.4 6.6 −48.9 31.31 −43.1 20.5 −66.0 23.2 2 −36.0 17.8 −71.8 26.0 3 −35.1 13.1 −60.5 20.24 −46.7 11.9 −64.3 18.2 5 −40.6 14.0 −55.5 25.8 6 −33.1 23.3 −57.3 18.07 −44.7 21.5 −47.1 23.9 24 −9.7 26.6 −41.5 17.3Model 2,

Experimental implementation: In rats which were under sodium thiopentalanesthesia, the spinal canal was opened and spinal medullary neuronswhich processed the “pain impulses” from the knee-joint were identified.Following identification, a long-term recording, in which the activityof the nerve cell was recorded before and during the development of anacute inflammation in the knee-joint, was carried out. For this, theresponses to non-noxious and noxious stimulation at the knee-joint weremeasured in a control period before inducing the inflammation and forseveral hours after inducing the inflammation.

The acute inflammation was induced by the intraarticular injection of asuspension (about 150 μl) of kaolin and carrageenan. In controlledexperiments, only the vehicle was applied to the spinal medullarysurface in order to represent the development of the hyperexcitabilityunder control conditions. As a rule, this development ofhyperexcitability took place within 2 to 4 hours and was expressed in amarked increase in the responses to non-noxious and noxious stimulationof the knee-joint (Tab. 3). In the experiments in which theabovementioned compound 13 was applied, the substance was added (about30 μl of a 10 μM solution) to the spinal medulla about 30 minutes beforeinducing the inflammation. The responses of the cell to non-noxious andnoxious stimulation were then subsequently monitored as in the controlexperiments.

Comparison of the changes in the responses in the two groups shows that,as compared with the controls, compound 13 almost completely suppressedthe development of spinal hyperexcitability (Tab. 3). Taken overall, theeffect of compound 13 on the responses to noxious knee-joint stimulationwas more strongly expressed than was the effect of indomethacin, as wasshown by a comparison with published data from an earlier study.

TABLE 3 Neuronal responses before and during knee-joint inflammation(imp/15 s) Time (min) after K/C Mean value SEM Mean value SEM injectionCompound 13 compound 13 control control Noxious stimulation at theknee-joint Baseline 0.8 29.9 0 0 30-60 62.3 49.3 161.6 43.7  60-120 26.935 458.1 125.4 120-180 8.5 58.9 544.2 140.0 180-240 19.5 59.9 616.3174.7 Non-noxious stimulation at the knee-joint Baseline 0.92 16.90 0 030-60 8.66 23.76 21.4 11.9  60-120 2.71 25.94 74.6 38.3 120-180 11.1624.22 105.7 39.0 180-240 39.78 25.09 149.7 44.3

The effect ofN-((S)-1-carbamoyl-2-diphenylaminoethyl)-2-(2-methylaminopyrimidin-4-yl)-1H-benzimidazole-5-carboxamide,termed compound 22 below, was also tested in model 2.

Control Data: see Table 3

TABLE 4 Neuronal responses before and during knee-joint inflammation(imp/15 s) Time (min) after K/C Compound 22 Compound 22 injectionExperiment 1 Experiment 2 Noxious stimulation at the knee-joint Baseline0 0 30-60 −109.1 −9.2  60-120 −101.1 120-180 −37.8 60 180-240 96.7Non-noxious stimulation at the knee-joint Baseline 0 0 30-60 −34.1 −30.6 60-120 −37.2 120-180 −32.1 50.3 180-240 68.7

The data verify the good effect of compound 22 in model 2.

3rd Model: Zymosan-Induced Paw Inflammation in the Mouse;

Parameter: Paw Withdrawal Time during Thermal Stimulation of the HindPaw. Experimental implementation: In short-term anesthesia usingisoflurane, 25 μl of a suspension containing 50 mg of zymosan/ml wereinjected into the right hind paw of the experimental animal. Thedevelopment of a hyperalgesia was then determined quantitatively asfollows:

Determining the Paw Withdrawal Time during Thermal Stimulation(Hargreave's Test; see above).

The experimental animal was placed in a transparent plastic chamberhaving a glass floor. As soon as the experimental animal was no longermoving, following the reconnaissance phase (about 5 min), an infraredlight source was positioned directly below the hind paw to be stimulatedand switched on. The lamp emitted focused infrared light of increasingintensity such that the skin temperature of the hind paw increasedalmost linearly. As soon as the animal withdrew the paw, the lampswitched itself off. The temperature of the paw at the time it iswithdrawn has just become unpleasant for the animal; this is referred toas the thermal pain threshold.

Shortly before the zymosan injection, and for from 7 to 14 days afterthe injection, the thermal pain threshold was determined once daily onthe right hind paw and left hind paw. Subsequently, the integral of thearea which was formed from the curves for the paw withdrawal times ofthe inflamed paw and the noninflamed paw (AUC, area between the curves,see tables 5 and 6) was determined as a measure of the hyperalgesia. Thelarger this value is, the more pronounced is the hyperalgesia, and thesmaller the value is in animals which are being given the substance, thegreater is the success of the therapy.

In a 7-day study, the zymosan injection induced pronounced thermalhyperalgesia in a control group (see vehicle, tab. 5). In the othergroups, the substance was administered for the first time one day afterthe zymosan injection, after marked thermal hyperalgesia had alreadydeveloped. Compound 13 was then administered orally twice daily for 7days, in each case at the rate of 25 or 75 mg/kg in HEC/lipofundin (1%HEC in lipofundin). Analysis of the paw withdrawal times during theentire period of the study (7 days) showed that, when the substance wasadministered, the AUC decreased in a dose-dependent manner. At singledoses of from 8.3 mg/kg and upwards, a significant therapeutic effectwas achieved as compared with the vehicle group (tab. 5). Compound 13exhibits very strong activity in the test model. A very high dose ofparacetamol was likewise administered twice daily to another group ofanimals which was taken through the experiment in parallel. Compound 13reduced the thermal hyperalgesia to a greater extent than didparacetamol (tab. 5).

TABLE 5 Thermal hyperalgesia during the seven days following zymosaninjection Standard Statistical error Number difference AUC of the of asmean value arithmetic animals compared [measure of mean per with thehyperalgesia] (SEM) group vehicle Vehicle 45.1 1.5 8 Paracetamol, 200mg/kg 24.6 4.1 8 yes Compound 13, 2.8 mg/kg 40.4 2.4 8 no Compound 13,8.3 mg/kg 32.3 2.2 8 yes Compound 13, 25 mg/kg 19.4 2.9 8 yes Compound13, 75 mg/kg 17.4 2.6 8 yes

In another study carried out on mice, the activity of compound 13 wascompared with that of the specific COX-2 inhibitor Celecoxib. The schemefor zymosan injection and dosing was identical to that in the previouslydescribed study. The only difference was that this additional study ranfor 14 days.

Once again, compound 13 was able to reduce thermal hyperalgesia in adose-dependent manner (tab. 6). In the experiment, compound 13 andCelecoxib had equally strong effects at the high dosage (tab. 6).

TABLE 6 Thermal hyperalgesia during the 14 days following zymosaninjection Standard Statistical error Number difference AUC of the of asmean value arithmetic animals compared [measure of mean per with thehyperalgesia] (SEM) group vehicle Vehicle 90.0 5.1 8 Celecoxib, 8.3mg/kg 79.9 5.9 5 no Celecoxib, 25 mg/kg 51.5 3.7 9 no Compound 13, 8.3mg/kg 64.5 5.0 5 yes Compound 13, 25 mg/kg 47.6 4.4 9 yes4th Model: Zymosan-Induced Paw Inflammation in the Mouse;Parameter: Spontaneous Running Performance in a Running Wheel. In thecage in which it is kept, the experimental animal has access to arunning wheel, the revolutions of which are recorded electronically.During the night hours, the C57/B6 mice use the running wheelvoluntarily and, after a one-week phase of acclimatization, cover onaverage 4 100 meters/night. After zymosan has been injected, thedistance run each night is reduced. This reduction in runningperformance is a valid parameter for a restriction in function which isdue to inflammation pain. Experimental implementation: After anacclimatization phase of one week, the distance run/24 hours wasmeasured in order to determine the base line. 25 μl of a suspensioncontaining 50 mg of zymosan/ml were then injected into the right hindpaw of the experimental animal during short-term anesthesia usingisoflurane. The distance run/24 hours was then determined during thefollowing seven days. In the analysis, the area under the curve for thevalues for the distance run was determined (AUC, tab. 7): the lower theAUC, the lower was the running performance during the week followinginjection of the zymosan. Compound 13 was administered twice daily for 7days, with the dose in each case being 25 or 75 mg/kg in HEC/lipofundin(1% HEC in lipofundin). The substance was administered for the firsttime on day 1 after injection of the zymosan.

In one study, the effect of compound 13 on running performance followingzymosan injection was compared with that of paracetamol. Adose-dependent increase in the distance run, which was significant ascompared with the vehicle group, was found in the case of both thehigher doses (tab. 7). By contrast, no improvement as compared with thevehicle group was achieved when paracetamol was used at an extremelyhigh dose (also 2 □ daily) (tab. 7).

TABLE 7 Running wheel activity during the seven days following zymosaninjection Standard Statistical error Number difference of the of asarithmetic animals compared AUC mean per with the mean value (SEM) groupvehicle Vehicle 108.8 12.5 8 Paracetamol, 200 mg/kg 187.2 42.7 8 noCompound 13, 2.8 mg/kg 131.1 23.3 8 no Compound 13, 8.3 mg/kg 142.1 29.18 no Compound 13, 25 mg/kg 216.7 58.5 8 yes Compound 13, 75 mg/kg 251.741.9 8 yes

1. A method for treating pain in a patient in need thereof, comprisingadministering to the patient a pharmaceutically effective amount of anIκB-kinase inhibitor of the compound of formula Ia:

or a stereoisomeric form thereof or a mixture of stereoisomeric forms inany ratio, or a physiologically tolerated salt thereof, wherein, E isCH; M is N; R21 is hydrogen, halogen, —(C₁-C₄)-alkyl, —CN, —CF₃, —OR¹⁵,wherein, R¹⁵ is hydrogen or —(C₁-C₄)-alkyl, —N(R¹⁵)—R¹⁶ wherein, R¹⁵ andR¹⁶ are, independently of each other, hydrogen or —(C₁ -C₄)-alkyl,—C(O)—R¹⁵, wherein, R¹⁵ is hydrogen or —(C ₁-C₄)-alkyl, or—S(O)_(x)—R¹⁵, wherein, x is zero, 1 or 2, and R¹⁵ is hydrogen or—(C₁-C₄)-alkyl; R31 is hydrogen, halogen, —(C₁ -C₄)-alkyl, —CN, —CF₃,—OR¹⁵, wherein, R¹⁵ is hydrogen atom or —(C₁-C₄)-alkyl, —N(R¹⁵)—R¹⁶wherein, R¹⁵ and R¹⁶ are, independently of each other, hydrogen or—(C₁-C₄)-alkyl, —C(O)—R¹⁵, wherein, R¹⁵ is hydrogen or —(C₁-C₄)-alkyl,or —S(O_(x)—R¹⁵, wherein, x is zero, 1 or 2, and R¹⁵ is hydrogen or—(C₁-C₄)-alkyl; R22 is a heteroaryl radical selected from3-hydroxypyrro-2,4-dione, imidazole, imidazolidine, imidazoline,indazole, isothiazole, isothiazolidine, isoxazole, 2-isoxazolidine,isoxazolidine, isoxazolone, morpholine, oxazole, 1,3,4-oxadiazole,oxadiazolidinedione, oxadiazolone, 1,2,3,5-oxathiadiazole-2-oxide,5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole,piperazine, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine,pyrimidine, tetrazole, thiadiazole, thiazole, thiomorpholine, triazoleand triazolone, wherein the heteroaryl radical is optionally substitutedone, two or three times by —C(O)—R¹⁵, wherein R¹⁵ is hydrogen or —(C₁-C₄)-alkyl, —(C₁-C₄)-alkyl, —O—R¹⁵, wherein R¹⁵ is hydrogen or—(C₁-C₄)-alkyl, —N(R¹⁵)—R¹⁶ , wherein R¹⁵ and R¹⁶ are, independently ofeach other, hydrogen or —(C₁-C₄)-alkyl, halogen, or a keto radical,—C(O)—R¹⁵, wherein R¹⁵ is hydrogen or —(C₁-C₄)-alkyl, —C(O)—OR¹⁵,wherein R¹⁵ is hydrogen or —(C₁-C₄)-alkyl, or —C(O)—N(R¹⁷)—R¹⁸, whereinR¹⁷ and R¹⁸ are, independently of each other,hydrogen,—(C₁-C₄)—alkyl—OH,—O—(C₁-C₄)-alkyl or —(C₁-C₄)-alkyl; R23 ishydrogen or —(C₁-C₄)-alkyl; and R24 is a heteroaryl radical selectedfrom pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole,thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxide,triazolones, oxadiazolones, isoxazolones, oxadiazolidinedione, tfiazole,3-hydroxypyrro-2,4-dione, 5-oxo-1,2,4-thiadiazole, pyridine, pyrazine,pyrimidine, indole, isoindole, indazole, phthalazine, quinoline,isoquinoline, quinoxaline, quinazoline, cinnoline, β-carboline and benzofused cyclopenta derivatives or cyclohexa derivatives of theseheteroaryl radicals, wherein the heteroaryl radical is optionallysubstituted, one, two or three times, independently of each other, by—(C₁ -C₅)-alkyl, —(C₁-C₅)-alkoxy, halogen, nitro, amino,trifluoromethyl, hydroxyl, hydroxy—(C₁-C₄)-alkyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or—(C₁-C₄)-alkoxycarbonyl, or an aryl radical selected from phenyl,naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyland 4-biphenylyl, anthryl and fluorenyl, wherein the aryl radical isoptionally substituted, one, two or three times, independently of eachother, by —(C₁-C₅)-alkyl, —(C₁-C₅)-alkoxy, halogen, nitro, amino,trifluoromethyl, hydroxyl, hydroxy—(C₁-C₄)-alkyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or—(C₁-C₄)-alkoxycarbonyl wherein, the pain is an acute pain selected froma group consisting of a pain following injury, a post operative pain, apain associated with an acute attack of gout, and an acute painfollowing jaw-bone surgical intervention.
 2. The method according toclaim 1, wherein, for formula Ia, E is CH; M is N; R21 is hydrogen,halogen, —(C₁-C₄)-alkyl, —CN, —CF₃, —OR¹⁵, wherein, R¹⁵ is hydrogen atomor —(C₁-C₄)-alkyl, —N(R¹⁵)—R¹⁶ wherein, R¹⁵ and R¹⁶ are, independentlyof each other, hydrogen or —(C₁-C₄)-alkyl, —C(O)—R¹⁵, wherein, R¹⁵ ishydrogen or —(C₁C₄)-alkyl, or —S(O)_(X—)R¹⁵ , wherein, x is zero, 1 or2, and R¹⁵ is hydrogen or —(C₁-C₄)-alkyl; R22 is a heteroaryl radicalselected from imidazole, isothiazole, isoxazole, 2-isoxazolidine,isoxazolidine, isoxazolone, 1,3,4-oxadiazole, oxadiazolidinedione,1,2,3,5-oxadiazolone, oxazole, 5-oxo-4,5-dihydro[1,3,4]oxadiazole,tetrazole, thiadiazole, thiazole, triazole and triazolone, wherein theheteroaryl radical is optionally substituted one, two or three times bya keto radical, halogen, or —(C₁-C₂)-alkyl, —C(O)—N(R¹⁷)—R¹⁸ , whereinR¹⁷ and R¹⁸ are hydrogen,—(C₁-C₂)-alkyl —OH, —O—(C₁-C₂)-alkyl, or—(C₁-C₄)-alkyl; R23 is hydrogen, methyl or ethyl; R24 is a heteroarylradical selected from unsaturated, partially saturated and completelysaturated rings which are derived from pyridine, pyrazine, pyrimidine,pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole,isoxazole, thiazole, triazole or isothiazole, wherein the heteroarylradical is optionally substituted, one, two or three times,independently of each other by —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxy, F, Cl,I, Br, nitro, amino, trifluoromethyl, hyd roxyl, hydroxy—(C₁-C₄)-alkyl,methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl,aminocarbonyl or—(C₁-C₄-alkoxycarbonyl, or phenyl, wherein, the phenylis optionally substituted one, two or three times, independently of eachother, by F, Cl, I, Br, CF₃, —OH, —(C ₁-C₄)-alkyl or (C₁-C₄)-alkoxy; andR31 is hydrogen, halogen, —(C₁-C₄)-alkyl, —CN, —CF₃, —OR¹⁵, wherein, R15is hydrogen atom or —(C₁-C₄)-alkyl, —N(R¹⁵ )—R¹⁶ wherein, R¹⁵ and R¹⁶are, independently of each other, hydrogen or —(C₁-C₄)-alkyl, —C(O)—R¹⁵, wherein, R¹⁵ is hydrogen or —(C₁-C₄)-alkyl, or —S(O)_(x)—R¹⁵, wherein,x is zero, 1 or 2, and R¹⁵ is hydrogen or —(C₁-C₄)-alkyl.
 3. The methodaccording to claim 1, wherein the compound of formula Ia is, wherein thecompound N-[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2-yl)ethyl]-2-(2-methylaminopyrimidin-4-yl)-1 H-indole-5-carboxamide.